Modeling the impact of preplanned dose titration on delayed response.

Dose titration becomes more and more common in improving drug tolerability as well as determining individualized treatment doses, thereby maximizing the benefit to patients. Dose titration starting from a lower dose and gradually increasing to a higher dose enables improved tolerability in patients as the human body may gradually adapt to adverse gastrointestinal effects. Current statistical analyses mostly focus on the outcome at the end-of-study follow-up without considering the longitudinal impact of dose titration on the outcome. Better understanding of the dynamic effect of dose titration over time is important in early-phase clinical development as it could allow to model the longitudinal trend and predict the longer term outcome more accurately. We propose a parametric model with two empirical methods of modeling the error terms for a continuous outcome with dose titrations. Simulations show that both approaches of modeling the error terms work well. We applied this method to analyze data from a few clinical studies and achieved satisfactory results.